Salmonella enhance chemosensitivity in tumor through connexin 43 upregulation

The use of preferentially replicating bacteria as oncolytic agents is one of the innovative approaches for the treatment of cancer. The capability of Salmonella to disperse within tumors and hence to delay tumor growth was augmented when combined with chemotherapy. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of Salmonella and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Following Salmonella treatment, dose- and time-dependent upregulation of connexin 43 (Cx43) expressions were observed. Moreover, Salmonella significantly enhanced gap intercellular communication (GJIC), as revealed by the fluorescent dye scrape loading assay. To study the pathway underlying these Salmonella-induced effects, we found that Salmonella induced a significant increase in mitogen-Activated protein kinases (MAPK) signaling pathways. The Salmonella-induced upregulation of Cx43 was prevented by treatment of cells with the phosphorylated p38 inhibitor, but not phosphorylated extracellular signal-regulated kinase (pERK) inhibitor or phosphorylated c-jun N terminal kinase (pJNK) inhibitor. Specific knockdown of Cx43 had an inhibitory effect on GJIC and resulted in a reduction of cell death after Salmonella and cisplatin treatment. Our results suggest that accumulation of Salmonella in tumor sites leads to increase Cx43 gap junction communication and enhances the combination of Salmonella and cisplatin therapeutic effects. What's new? Bacteria such as Salmonella have been studied as antitumor agents, and are known to activate the expression of the gap-junction protein Cx43 in tumor cells. Salmonella also enhances the effect of chemotherapy drugs, but the molecular mechanism of this additive effect has not been understood. In this study, the authors found that the bacteria not only cause increased intercellular communication between tumor cells due to Cx43 upregulation, but also increase mitogen-Activated protein kinases (MAPK) signaling pathways. Salmonella presumably enhances the response to chemotherapy agents by increasing the passage of these drugs between neighboring tumor cells.